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Studying Adipose Endothelial Cell/Adipocyte Cross-Talk in Human Subcutaneous Adipose Tissue

Microvascular endothelial cells (MVECs) have many critical roles, including control of vascular tone, regulation of thrombosis, and angiogenesis. ...

University of Leeds

Changes in composition of the intestinal microbiota are linked to the development of obesity and can lead to endothelial cell (EC) dysfunction. It is unknown whether EC can directly influence the microbiota. Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are critical for coupling nutritional status and cellular growth; IGF-1R is expressed in multiple cell types including EC. The role of ECIGF-1R in the response to nutritional obesity is unexplored. To examine this, we use gene-modified mice with EC-specific overexpression of human IGF-1R (hIGFREO) and their wild-type littermates. After high-fat feeding, hIGFREO weigh less, have reduced adiposity and have improved glucose tolerance. hIGFREO show an altered gene expression and altered microbial diversity in the gut, including a relative increase in the beneficial genus Akkermansia. The depletion of gut microbiota with broad-spectrum antibiotics induces a loss of the favourable metabolic differences seen in hIGFREO mice. We show that IGF-1R facilitates crosstalk between the EC and the gut wall; this crosstalk protects against diet-induced obesity, as a result of an altered gut microbiota.

Endothelial IGF-1 receptor mediates crosstalk with the gut wall to regulate microbiota in obesity.

The vascular endothelium traditionally viewed as a simple physical barrier between the circulation and tissue is now well-established as a key organ mediating whole organism homeostasis by release of a portfolio of anti-inflammatory and pro-inflammatory vasoactive molecules. Healthy endothelium releases anti-inflammatory signaling molecules such as nitric oxide and prostacyclin; in contrast, diseased endothelium secretes pro-inflammatory signals such as reactive oxygen species, endothelin-1 and tumor necrosis factor-alpha (TNFα). Endothelial dysfunction, which has now been identified as a hallmark of different components of the cardiometabolic syndrome including obesity, type 2 diabetes and hypertension, initiates and drives the progression of tissue damage in these disorders. Recently it has become apparent that, in addition to vasoactive molecules, the vascular endothelium has the potential to secrete a diverse range of small molecules and proteins mediating metabolic processes in adipose tissue (AT), liver, skeletal muscle and the pancreas. AT plays a pivotal role in orchestrating whole-body energy homeostasis and AT dysfunction, characterized by local and systemic inflammation, is central to the metabolic complications of obesity. Thus, understanding and targeting the crosstalk between the endothelium and AT may generate novel therapeutic opportunities for the cardiometabolic syndrome. Here, we provide an overview of the role of the endothelial secretome in controlling the function of AT. The endothelial-derived metabolic regulatory factors are grouped and discussed based on their physical properties and their downstream signaling effects. In addition, we focus on the therapeutic potential of these regulatory factors in treating cardiometabolic syndrome, and discuss areas of future study of potential translatable and clinical significance. The vascular endothelium is emerging as an important paracrine/endocrine organ that secretes regulatory factors in response to nutritional and environmental cues. Endothelial dysfunction may result in imbalanced secretion of these regulatory factors and contribute to the progression of AT and whole body metabolic dysfunction. As the vascular endothelium is the first responder to local nutritional changes and adipocyte-derived signals, future work elucidating the changes in the endothelial secretome is crucial to improve our understanding of the pathophysiology of cardiometabolic disease, and in aiding our development of new therapeutic strategies to treat and prevent cardiometabolic syndrome.

Cheukyau Luk

Leeds Institute of Cardiovascular and Metabolic Medicine

University of Leeds

Studying Adipose Endothelial Cell/Adipocyte Cross-Talk in Human Subcutaneous Adipose Tissue

Cheukyau Luk

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University of Leeds

Studying Adipose Endothelial Cell/Adipocyte Cross-Talk in Human Subcutaneous Adipose Tissue

Leeds Institute of Cardiovascular and Metabolic Medicine